Cancer is a leading cause of mortality and morbidity. Approaches to treating cancer include surgical intervention to remove tumors and chemotherapy. These approaches can successful cure some patients. However, even patients that appear to have been cured often suffer a recurrence of the cancer necessitating further therapy. Chemotherapeutic agents generally are nonselective agents that are toxic to cells, such as proliferating cells. Accordingly, such agents may effectively kill cancer cells but also kill health cells producing sever deleterious side effects.
Certain cancer cells express or overexpress certain cellular components such as cell surface proteins, or express different cellular components when compared to normal cells. One approach to address the short comings of surgical and chemotherapeutic approaches to cancer therapy and diagnosis involves targeting cancer cells, for example using antibodies or antibody fragments that bind to proteins that are expressed or overexpressed on cancerous cells. A number of such target proteins have been identified. Amoung such proteins is the epidermal growth factor receptor (EGFR).
EGFR is a member of the ErbB1 family and transduces signals that lead to cellular proliferation and survival, and the elaboration of motailtiy, growth and angiogenic factors upon binding epidermal growth factor (EGF) and or transforming growth factor alpha (TGF alpha). Accordingly, EGFR has been demonstrated to be involved in tumor growth, metastasis and angiogenesis. Further many cancer express EGFR, such as bladder cancer, ovarian cancer, colorectal cancer, breast cancer, lung cancer (e.g., non-small cell lung carcinoma), gastric cancer, pancreatic cancer, prostate cancer, head and neck cancer, renal cancer and gall bladder cancer. ERBITUX (cetuximab; Imclone Systems Inc) is a chimeric mouse/human antibody that binds human EGFR that has been approved for treating certain EGFR-expressing cancers in combination with irinotecan.
An important pathophysiological process that facilitates tumor formation, metastasis and recurrence is tumor angiogenesis. This process is mediated by the elaboration of angiogenesis factors by the tumor, such as vascular endothelial growth factor (VEGF), which induce the formation of blood vessels that deliver nutrients to the tumor. Accordingly, another approach to treating certain cancers is to inhibit tumor angiogenesis mediated by VEGF, thereby starving the tumor. AVISTIN (bevacizumab; Genetech, Inc.) is a humanized antibody that binds human VEGF that has been approved for treating colorectal cancer. An antibody referenced to as antibody 2C3 (ATCC Accession No. PTA 1595) is reported to bind VEGF and inhibit binding of VEGF to epidermal growth factor receptor 2.
Targering EGFR or VEGF with currently available therapeutics is not effective in all patients, or for all cancers (e.g., EGFR-expressing cancers). Thus, a need exists for improved agents for treating cancer and other pathological conditions.